Pharmaceutical Composition

ABSTRACT

The present invention relates to the field of pharmacy, particularly to a pharmaceutical composition for oral administration comprising an (a) inert substrate and a (b) mixture comprising a non-bile acid farnesoid X receptor (FXR) agonist, such as 2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof, and at least one binder. The present invention also relates to a process for preparing said pharmaceutical composition for oral administration; and to the use of said pharmaceutical composition in the manufacture of a medicament.

FIELD OF THE INVENTION

The present invention relates to the field of pharmacy, particularly toa pharmaceutical composition for oral administration comprisingparticles, wherein said particles comprise an inert substrate, a mixturecomprising a non-bile acid farnesoid X receptor (FXR) agonist, such as2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid, or apharmaceutically acceptable salt thereof, and at least one binder. Thepresent invention also relates to a pharmaceutical compositioncomprising a non-bile acid farnesoid X receptor (FXR) agonist, such as2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid or apharmaceutically acceptable salt thereof, and another activepharmaceutical ingredient. The present invention also relates to aprocess for preparing said pharmaceutical composition for oraladministration; and to the use of said pharmaceutical composition in themanufacture of a medicament.

BACKGROUND OF THE INVENTION

Nuclear receptors constitute a superfamily of transcriptional regulatoryproteins that share structural and functional properties and function asreceptors for example steroids, retinoids, vitamin D, and thyroidhormones (Evans et al. Science 1988, 240, 889). The farnesoid X receptor(FXR) is a member of the nuclear hormone receptor superfamily and isprimarily expressed in the liver, kidney and intestine (Seol et al. Mol.Endocrinol. 1995, 9, 72-85; Forman et al. Cell 1995, 81, 687-693). Itfunctions as a heterodimer with the retinoid X receptor (RXR) and bindsto response elements in the promoters of target genes to regulate genetranscription. The FXR-RXR heterodimer binds with highest affinity to aninverted repeat-1 (IR-1) response element, in which consensusreceptor-binding hexamers are separated by one nucleotide. FXR is partof an interrelated process, in that FXR is activated by bile acids (theend product of cholesterol metabolism) (Makishima et al. Science 1999,284, 1362-1365; Parks et al. Science 1999, 284, 1365-1368; Wang et al.Mol. Cell. 1999, 3, 543-553), which serve to inhibit cholesterolcatabolism (Urizar et al. J. Biol. Chem. 2000, 275, 39313-39317). FXRagonists have been explored as therapeutics against non-alcoholicsteatohepatitis (NASH).

The specific non-bile acid FXR agonist2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof, is referred toherein as Compound (A). The present invention also relates to:

The compound was disclosed for the first time in WO 2012/087519 (Example1, compound 1-IB of the table on page 125) and it is also known underthe name LJN452 and under its International Nonproprietary Name (INN)“Tropifexor”. Said compound may be used for the treatment of an FXRmediated disease or disorder. There is a need to provide a commerciallyviable pharmaceutical composition comprising2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof.

In addition, the following classes of compounds or therapeutics havebeen explored to mediate metabolic dysfunctions: glucagon-like peptide 1(GLP-1) receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 (DPP4)inhibitors, peroxisome proliferator-activated receptor (PPARs) agonists,acetyl-CoA carboxylase (ACC) inhibitors, thyroid hormone receptor β(TRβ) agonists, ketohexokinase (KHK) inhibitors, diacylglycerolAcyltransferase 2 (DGAT2) inhibitors, and sodium-glucose linkedtransporter (SGLT) inhibitors.

Other related targets and agents include: anti-inflammatory agents (suchas chemokine receptor 2/5 (CCR2/5) antagonists), and anti-fibrosisagents (such as Galectin-3 inhibitors and Lysyl oxidase-like 2 (LOXL 2)inhibitors).

Because the pathophysiology of NAFLD and NASH is complex and multipleredundant pathways may be implicated, there is a need to providetreatments for nonalcoholic fatty liver disease (NAFLD), NASH andfibrotic/cirrhotic that can address the different aspects of thesecomplex conditions, while demonstrating an acceptable safety and/ortolerability profile.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the dissolution profile for Capsule (C1) comprising 0.03 mgCompound (A), as disclosed herein, (500 mL and 900 mL vessels volume).

FIG. 2 shows the dissolution profile for Capsule (C2) comprising 0.16 mgCompound (A) (900 mL vessels volume).

FIG. 3 shows the dissolution profile for tablets comprising Formulation5 (F5) and Formulation 6 (F6) with 0.03 mg of Compound (A), as disclosedherein, compressed at lowest and highest compression forces relative tothe dry blend capsule formulation (0.1 mg release profile).

FIG. 4 shows the dissolution profile for tablets comprising Formulation5 (F5) and Formulation 6 (F6) with 0.03 mg of Compound (A), as disclosedherein, compressed at lowest and highest compression forces relative tothe dry blend capsule formulation (0.1 mg release profile).

FIG. 5 shows the XRPD diffractograms of the lactose, the common blend ofFormulation 6 (F6) and the seal coated Formulation 2 (F2s).

FIG. 6 shows the DSC thermograms obtained for the seal coatedFormulation 2 (F2s).

FIG. 7 shows the particle size distribution (PSP) of the seal coatedFormulation 2 (F2s).

FIG. 8 shows the particle size distribution (PSP) of the tablet blend ofFormulation 6 (F6) of the sealed coated tablet formulation comprisingCompound (A).

FIG. 9 shows the SEM analysis of Lactose (inert substrate withoutCompound (A)) at 5 μm.

FIG. 10 shows the SEM analysis of the Formulation 2 (F2) at 5 μm.

FIG. 11 shows the SEM analysis of the Formulation 2 (F2) at 100 μm

FIG. 12 shows the SEM analysis of the seal coated Formulation 2 (F2s) at100 μm.

FIG. 13 shows the SEM analysis of the Formulation 2 (F2s) at 20 μm.

FIG. 14 shows the SEM analysis of the sealed coated Formulation 2 (F2s)at 20 μm.

FIG. 15 shows the surface Raman mapping of the sealed coated Formulation2 (F2s) at 10 μm resolution.

FIG. 16 shows the surface Raman mapping of sealed coated Formulation 2(F2s) at 20 μm resolution.

FIG. 17 shows the Raman Spectra comparing crystalline and amorphousCompound (A), with Compound (A) in the Formulation 2 (F2) (0-1777 cm⁻¹range).

FIG. 18 shows the average plasma concentration over time for Compound(A) in different formulations in the dog.

SUMMARY OF THE INVENTION

The design of a pharmaceutical composition, a pharmaceutical dosageform, as well as a commercially viable process to prepare thepharmaceutical composition, for a non-bile acid FXR agonist, such as2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof (herein Compound(A)) is especially challenging. This non-bile acid FXR agonist is ahighly potent active pharmaceutical ingredient (API) classified by thebiopharmaceutical classification system as a class IV compound, e.g.poorly soluble and poorly permeable compound. Moreover, this non-bileacid FXR agonist is difficult to formulate due to its physicochemicalproperties and its high potency. Finding a suitable pharmaceuticalcomposition, in a reliable and robust way, proved challenging. Forexample, due to its very high potency a low dosage is needed(sub-milligrams or micrograms), generating unwanted formulation issuessuch as content uniformity, and additional manufacturing difficulties,particularly when practiced on a larger manufacturing scale.Furthermore, this non-bile acid FXR agonist has a low water solubilityand mixing the compound with conventional excipients to provide aneffective composition proved difficult (owing to instability of theformulation, unpredictable dissolution rates and variablebioavailability). Accordingly, a suitable and robust solidpharmaceutical composition overcoming the above problems needs to bedeveloped.

In view of the above-mentioned difficulties, and considerations, it wassurprising to find a way to prepare a stable pharmaceutical compositionthat allows the preparation of a pharmaceutical composition comprisinglow amounts of the active compound, avoiding any content uniformity ormanufacturing issues.

In one aspect the present invention relates to a pharmaceuticalcomposition for oral administration comprising (a) an inert substrate,and (b) a mixture comprising2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof, and at least onebinder.

In one aspect the present invention relates to a pharmaceuticalcomposition for oral administration comprising particles, wherein saidparticles comprise (a) an inert substrate, and (b) a mixture comprising2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof, and at least onebinder.

Aspects, advantageous features and preferred embodiments of the presentinvention summarized in the following items, respectively alone or incombination, contribute to solving the object of the invention.

Item A1. A pharmaceutical composition for oral administration comprisingparticles, wherein said particles comprise (a) an inert substrate, and(b) a mixture comprising2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid,or a pharmaceutically acceptable salt thereof, and at least one binder.

Item A2. The pharmaceutical composition according to item A1, wherein2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof, is in amorphousform, crystalline form, or a mixture thereof.

Item A3. The pharmaceutical composition according to item A1 to A2,wherein2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid is a free form.

Item A4. The pharmaceutical composition according to items A1 to A3,wherein the (b) mixture comprising2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof, and at least onebinder, is dispersed onto the (a) inert substrate.

Item A5. The pharmaceutical composition according to items A1 to A3,wherein the (a) inert substrate is coated with the (b) mixturecomprising2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof, and at least onebinder.

Item A6. The pharmaceutical composition according to any one of items A1to A5, wherein the (a) inert substrate comprises a material which isselected from the group consisting of lactose, microcrystallinecellulose, mannitol, sucrose, starch, granulated hydrophilic fumedsilica, or mixtures thereof.

Item A7. The pharmaceutical composition according to any one of items A1to A6, wherein the binder is selected from the group consisting ofpolyvinyl pyrrolidone, hydroxypropyl cellulose, hypromellose,carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose,carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose,polyethylene glycol, polyvinylalcohol, shellac, polyvinylalcohol-polyethylene glycol co-polymer, or a mixtures thereof.

Item A8. The pharmaceutical composition according to any one of items A1to A7, wherein the particles further comprises an outer (c) seal coatinglayer.

Item A9. The pharmaceutical composition according to any one of items A1to A8, wherein the outer (c) seal coating layer is selected from thegroup consisting of hydroxypropyl methyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, carboxymethyl cellulose, methylcellulose, hydroxyethyl cellulose, carboxyethyl cellulose,carboxymethylhydroxyethyl cellulose, polyethylene glycol,polyvinylalcohol, or mixtures thereof.

Item A10. The pharmaceutical composition according to any one of itemsA1 to A9, wherein the particles are further formulated into a finaldosage form, optionally in the presence of at least one pharmaceuticallyacceptable excipient, and wherein said final dosage form is a capsule, atablet, a mini-tablet, a sachet, or a stickpack.

Item A11. The pharmaceutical composition according to item A10, whereinthe final dosage form is a capsule or a tablet.

Item A12. The pharmaceutical composition according to any one of itemsA1 to A11, comprising at least one further active pharmaceuticalingredient.

Item A13. The pharmaceutical composition according to any one of itemsA1 to A12, wherein the final dosage form comprises2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof, in an amount ofabout 0.01 mg to about 2 mg.

Item A14. A process for preparing the pharmaceutical composition fororal administration, as defined in items A1 to A13, said processcomprising the steps of:

-   -   (i) Mixing the (b) mixture comprising        2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic        acid, or a pharmaceutically acceptable salt thereof, with at        least one binder, and optionally with at least one polar protic        solvent, and    -   (ii) Adding said mixture (i) to the (a) inert substrate of the        particles.

Item A15. The process according to item A14, wherein the at least oneprotic polar solvent is selected from the group consisting of organicsolvents, water, or mixtures thereof.

Item A16. The process according to item A15, wherein the organic solventis selected from the group consisting of methanol, ethanol, isopropanol,n-propanol, n-butanol, or mixtures thereof.

Item A17. The process according to item A16, wherein the organic solventis ethanol.

Item A18. The process according to items A14 to A17, wherein the solventis removed at a temperature of 20° C. to 130° C.

Item A19. The process according to items A14 to A18, wherein the mixtureof step (i) is dispersed onto the (a) inert substrate.

Item A20. The process according to any one of items A14 to A18, whereinthe (a) inert substrate is coated with the mixture of step (i).

Item A21. The process according to any one of items A14 to A20, furthercomprising the step of adding an outer (c) seal coating layer onto saidparticles.

Item A22. The process according to any one of items A14 to A21,comprising the step of further adding at least one additional activepharmaceutical ingredient.

Items A23. The process according to any one of items A14 to A22, furthercomprising preparing the final dosage form by optionally mixing theparticles with at least one pharmaceutically acceptable excipient.

Items A24. The process according to any one of items A14 to A23, whereinthe at least one pharmaceutically acceptable excipient is selected fromthe group consisting of lactose, mannitol, microcrystalline cellulose,dicalcium phosphate, polyvinyl pyrrolidone, hydroxypropylmethylcellulose, croscarmellose sodium, crospovidone, sodium starchglycolate, colloidal silicon dioxide, magnesium stearate, sodium stearylfumarate, or mixtures thereof.

Item A25. The process according to any one of items A14 to A24, whereinthe final dosage form is encapsulated or tableted.

Item A26. A process for preparing a suspension comprising mixing the (b)mixture comprising2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof, and at least onebinder, with water.

Item A27. A process for preparing a dispersible solution comprisingmixing the (b) mixture comprising2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof, and at least onebinder, with an organic solvent.

Item A28. A solid dispersion comprising2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof, and at least onebinder.

Item A29. A dispersible solution comprising2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof, and at least onebinder, in an organic solvent.

Item A30. The pharmaceutical composition according to any one of itemsA1 to A13, for use as a medicine.

Item A31. The pharmaceutical composition according to any one of itemsA1 to A13, for use in the treatment of cholestasis, intrahepaticcholestatis, estrogen-induced cholestasis, drug-induced cholestasis,cholestasis of pregnancy, parenteral nutrition-associated cholestasis,primary biliary cirrhosis (PBC), non-alcoholic fatty liver disease(NAFLD), non-alcoholic steatohepatitis (NASH), liver cirrhosis,alcohol-induced cirrhosis, cystic fibrosis, or liver fibrosis,preferably for primary biliary cirrhosis (PBS) or non-alcoholicsteatohepatitis (NASH).

Item A32. Use of the pharmaceutical composition for oral administrationas defined in items A1 to A13, for the manufacture of a medicament forcholestasis, intrahepatic cholestatis, estrogen-induced cholestasis,drug-induced cholestasis, cholestasis of pregnancy, parenteralnutrition-associated cholestasis, primary biliary cirrhosis (PBC),non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis(NASH), liver cirrhosis, alcohol-induced cirrhosis, cystic fibrosis, orliver fibrosis, preferably for primary biliary cirrhosis (PBS) ornon-alcoholic steatohepatitis (NASH).

Item A33. A pharmaceutical composition for oral administrationcomprising (a) an inert substrate, and (b) a mixture comprising2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid,or a pharmaceutically acceptable salt thereof, and at least one binder.

Item A34. The pharmaceutical composition according to any one of itemsA1 to A13, and A33, wherein the inert substrate is present in an amountfrom about 16-fold w/w to about 6400-fold w/w, from about 100-fold w/wto about 3200-fold w/w, from about 400-fold w/w to about 1600-fold w/w,from about 800-fold w/w to about 1200-fold w/w, from about 900-fold w/wto about 1000-fold w/w based on an amount of the2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid,or a pharmaceutically acceptable salt thereof.

Item A35. The pharmaceutical composition according to any one of itemsA1 to A13, A33, and A34, wherein the inert substrate is present in anamount about 100-fold w/w, about 300-fold w/w, about 500-fold w/w, about600-fold w/w, about 700-fold w/w, about 800-fold w/w, about 900-foldw/w, about 1000-fold, about 1200-fold w/w, about 1500-fold w/w based onan amount of the2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid,or a pharmaceutically acceptable salt thereof.

Item A36. The pharmaceutical composition according to any one of itemsA1 to A13, A33 to A35, wherein the at least one binder in the (b)mixture is present in an amount from about 0.5-fold w/w to about300-fold w/w, from about 1-fold to about 150 fold w/w, from about10-fold w/w to 100-fold w/w, from 25-fold w/w to about 75-fold w/w, orfrom about 40-fold w/w to about 60-fold w/w based on an amount of the2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid,or a pharmaceutically acceptable salt thereof.

Item A37. The pharmaceutical composition according to any one of itemsA1 to A13, A33 to A36, wherein the binder is polyvinyl pyrrolidone.

Item A38. The pharmaceutical composition according to any one of itemsA1 to A13, A33 to A37, wherein the binder is present in an amount fromabout 10-fold w/w to about 100-fold w/w, or about 50-fold w/w based onan amount of the2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid,or a pharmaceutically acceptable salt thereof.

Item A39. The pharmaceutical composition according to any one of itemsA1 to A13, A33 to A38, wherein2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid,or a pharmaceutically acceptable salt thereof is present in an amountfrom about 0.05% w/w to about 2.5% w/w, from about 0.07% w/w to about 2%w/w, from about 0.08% w/w to about 1% w/w, from about 0.09% w/w to about0.5% w/w, or from about 0.1% w/w to about 0.25% w/w relative to a weightof the pharmaceutical composition.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides Composition Comprising Compound Acontaining Compound A in low amounts. In one embodiment, CompositionComprising Compound A is directly processed into final dosage forms.

In another embodiment, at least one further active pharmaceuticalingredient Compound (B) is combined with Compound A in a dosage form.Compound (B) is introduced via Composition Comprising Compound B.Compound B can be a solid, or a liquid. Thus, Composition ComprisingCompound B can be a particle, a granule, a dispersion (solid or liquid),a tablet, a mini-tablet, a bead, a pellet, a solution, or a mixturethereof. Composition Comprising Compound B can be combined withComposition Comprising Compound A to form Composition ComprisingCompounds A and B which is then processed into final dosage forms.

Composition Comprising Compound A

The effective formulation of a low dose non-bile acid FXR agonist, suchas2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof, (Compound (A), asdisclosed herein), proved difficult. For example, difficulties inweighing the low amount of non-bile acid FXR agonist, contentuniformity, formulation, dissolution rate and bioavailability issueswere observed. Ultimately, those issues were affecting the manufacturingprocess and in vivo performance of the pharmaceutical composition.

Surprisingly, it was found that those challenges can be overcome bypreparing a pharmaceutical composition for oral administrationcomprising (a) an inert substrate, and (b) a mixture comprising anon-bile acid FXR agonist, and at least one binder. According to thepresent disclosure, the non-bile acid FXR agonist is2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid, or apharmaceutically acceptable salt thereof (Compound (A)).

In one aspect, the pharmaceutical composition for oral administration ofthe present invention is a particle.

In one aspect the present invention provides a pharmaceuticalcomposition for oral administration comprising particles, wherein saidparticles comprise (a) an inert substrate, and (b) a mixture comprisingCompound (A)(2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof), and at least onebinder.

According to the present invention, Compound (A) can also be present inits free form. The Compound (A), as described herein, may also bepresent in a crystalline form, in an amorphous form, or a mixturethereof.

In another aspect, the present invention also provides a pharmaceuticalcomposition for oral administration comprising (a) an inert substrate,and (b) a mixture comprising a non-bile acid FXR agonist, and at leastone binder. According to the present disclosure, the non-bile acid FXRagonist is2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid, or apharmaceutically acceptable salt thereof (Compound (A)).

According to the present invention, the pharmaceutical compositioncomprises an (a) inert substrate on which the (b) mixture comprisingCompound (A), and at least one binder, is added. The (a) inert substratecomprises a material that does not chemically react to the (b) mixturecomprising Compound (A), and at least one binder. The (a) inertsubstance is, for example, a pharmaceutically acceptable excipient knownin the art not to interact chemically or physically with the activesubstance. Optionally, the (a) inert substrate can also be coated with alayer to protect the (a) inert substrate from any unwanted chemical orphysical interaction that may happen during the formulation process.Optionally, the (a) inert substrate can also be treated with anacceptable excipient (for example, a binder) to render certain desirableprocess qualities, such as particle size and flowability, to the inertsubstance. The (a) inert substrate may comprise a material, which isselected from the group consisting of lactose, microcrystallinecellulose, mannitol, sucrose, starch, granulated hydrophilic fumedsilica, tartaric acid, or mixtures thereof. Preferably, the material maycomprise a material selected from the group consisting of lactose,microcrystalline cellulose, mannitol, sucrose, starch, granulatedhydrophilic fumed silica, or mixtures thereof. More preferably, thematerial is lactose, or mannitol. The inert substrate can be present inan amount from about 16-fold w/w to about 6400-fold w/w, from about100-fold w/w to about 3200-fold w/w, from about 400-fold w/w to about1600-fold w/w, from about 800-fold w/w to about 1200-fold w/w, fromabout 900-fold w/w to about 1000-fold w/w based on the amount ofCompound (A). In one embodiment, the inert substrate is present in anamount about 100-fold w/w, about 300-fold w/w, about 500-fold w/w, about600-fold w/w, about 700-fold w/w, about 800-fold w/w, about 900-foldw/w, about 1000-fold, about 1200-fold w/w, about 1500-fold w/w based onthe amount of Compound (A) or a pharmaceutically acceptable saltthereof.

Suitable binders for the (a) inert substance or the (b) mixture can beselected, for example, but not limited to, from the group consisting ofcellulose acetate, cellulose fatty acid ester, cellulose nitrates (e.g.nitrocelluloses, nitrowools, Collodion), cellulose ether, ethylcellulose, carboxymethyl cellulose (e.g. sodium cellulose gum, cellulosegum), methyl cellulose (e.g. cellulose methyl ether, Tylose),methylethyl cellulose, methylhydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, hypromellose (HPMC), hydroxyethylcellulose, carboxyethyl cellulose, carboxymethyl hydroxyethyl cellulose,polyethylene glycol, polyvinyl alcohol, shellac, polyvinylalcohol-polyethylene glycol co-polymer, or mixtures thereof. Preferably,the binder is selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl cellulose, hypromellose, carboxymethylcellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethylcellulose, carboxymethyl hydroxyethyl cellulose, polyethylene glycol,polyvinylalcohol, shellac, polyvinyl alcohol-polyethylene glycolco-polymer, or mixtures thereof. More preferably, the binder ispolyvinyl pyrrolidone (PVP).

The at least one binder present in the (b) mixture can be present in anamount from about 0.5-fold w/w to about 300-fold w/w, from about 1-foldto about 150 fold, from about 10-fold w/w to 100-fold w/w, from 25-foldw/w to about 75-fold w/w, or from about 40-fold w/w to about 60-fold w/wbased on the amount of Compound (A), or a pharmaceutically acceptablesalt thereof. The above-mentioned ranges apply for all the binders aslisted above. Preferably, the binder is polyvinyl pyrrolidone.Preferably, the binder is present in an amount from about 10-fold w/w toabout 100-fold w/w, from about 25-fold w/w to about 75-fold w/w, or fromabout 40-fold w/w to about 60-fold w/w based on the amount of Compound(A). More preferably, the binder is present in an amount about 50-foldw/w based on the amount of Compound (A), or a pharmaceuticallyacceptable salt thereof.

In accordance with the present invention, the (b) mixture comprisingCompound (A), and at least one binder, can be added onto the (a) inertcore using different techniques known in the art. For example, the (a)inert core can be sprayed or coated with the (b) mixture, using, forexample, spray drying, spray layering, spray dispersing, spray coating,fluid bed drying, fluid bed coating, granulators with spray nozzles, ora combination of those spraying techniques thereof. Preferably, the (b)mixture comprising Compound (A), and at least one binder, is dispersedonto the (a) inert substrate. In another preferred aspect, the (a) inertsubstrate is coated with the (b) mixture comprising Compound (A), and atleast one binder. The (b) mixture comprising Compound (A), and at leastone binder, is preferably dispersed or coated onto the (a) inert core asdiscrete particles, thus, providing a large surface area for instantdissolution despite the poor solubility of the drug. As a result, a fastdissolution rate of Compound (A) can be achieved.

In accordance with the aspect of the present invention, the particle, asdefined herein, optionally further comprises an outer (c) seal coatinglayer. The outer (c) seal coating layer comprises a material that doesnot chemically react with the (b) mixture comprising Compound (A), andat least one binder, and protects the (b) mixture, as defined herein,from any unwanted chemical or physical interaction that may happenduring the formulation process, e.g. with additives, pharmaceuticallyacceptable excipients, or any further active pharmaceutical ingredient.The outer (c) seal coating layer also provides an additional barrier fortaste masking. The outer (c) seal coating layer can also provide abarrier for gastric or stomach release while allowing for enteric orintestinal release. The outer (c) seal coating layer comprises, forexample, hydroxypropyl methyl cellulose (HPMC), magnesium stearate,polyvinyl pyrrolidone, hydroxypropyl cellulose, carboxymethyl cellulose,methyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose,carboxymethylhydroxyethyl cellulose, polyethylene glycol,polyvinylalcohol, cellulose acetate phthalates (CAP), cellulose acetatetrimellitates (CAT), hydroxypropyl methyl cellulose phthalates (HPMCP),hydroxypropyl methyl cellulose acetate succinate (HPMCAS), polyvinylacetate phthalate (PVAP), methyl methacrylate-methacrylic acidcopolymers, cellulose acetate succinate, fatty acids, waxes, shellac,sodium alginate, zein, or mixtures thereof. The outer (c) seal coatinglayer comprises, for example, hydroxypropyl methyl cellulose, magnesiumstearate, polyvinyl pyrrolidone, hydroxypropyl cellulose, carboxymethylcellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethylcellulose, carboxymethylhydroxyethyl cellulose, polyethylene glycol,polyvinylalcohol, or mixtures thereof. Preferably, the outer (c) sealcoating layer comprises magnesium stearate, hydroxypropyl methylcellulose, or mixtures thereof. More preferably, the material used forthe outer (c) seal coating layer is hydroxypropyl methyl cellulose(HPMC).

The material used for the outer (c) seal coating layer can be present inan amount of about 0.5% w/w to about 6% w/w based on the total weight ofthe particles. Preferably, in an amount of 1% w/w to about 5% w/w basedon the total weight of the particles. More preferably, in an amount ofabout 3% w/w based on the total weight of the particles. Theabove-mentioned ranges apply to all outer (c) seal coating layermaterials as listed above.

According to the present invention, the size of the particle correspondsto the size of the (a) inert substrate, as disclosed herein, togetherwith the coating. For example, the particle can have a size from about20 μm to about 500 μm. Preferably, the particle can have a size fromabout 50 μm to 400 μm. More preferably, the particle can have a size ofabout 100 μm to about 300 μm. The particle size is measured, forexample, by laser diffraction methodology (e.g. particle sizedistribution (PSD)). For example, the particle size is measured usingthe instrument and method disclosed herein.

A further aspect of the present invention provides a process forpreparing the pharmaceutical composition for oral administration, saidprocess comprising the steps of:

(i) Mixing the (b) mixture comprising Compound (A)(2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof), with at least onebinder, as defined herein, and optionally with at least one polar proticsolvent, as defined herein; and

(ii) Adding said mixture (i) to the (a) inert substrate, as definedherein.

A further aspect of the present invention provides a process forpreparing the pharmaceutical composition for oral administration, saidprocess comprising the steps of:

(i) Mixing the (b) mixture comprising Compound (A)(2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof), with at least onebinder, as defined herein, and optionally with at least one polar proticsolvent, as defined herein; and

(ii) Adding said mixture (i) to the (a) inert substrate, as definedherein, wherein said polar protic solvent, when present, is removed at atemperature of about 20° C. to about 130° C. Preferably, the polarprotic solvent is removed at a temperature of about 50° C. to about 110°C. More preferably, at a temperature of about 70° C. to about 100° C.

A further aspect of the present invention provides a process forpreparing the pharmaceutical composition for oral administrationcomprising particles, as defined herein, said process comprising thesteps of:

(i) Mixing the (b) mixture comprising Compound (A)(2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof), with at least onebinder, as defined herein, and optionally with at least one polar proticsolvent, as defined herein; and

(ii) Adding said mixture (i) to the (a) inert substrate of theparticles, as defined herein.

The pharmaceutical composition can comprise particles comprisingCompound (A), wherein compound (A) is present from about 0.05% w/w toabout 2.5% w/w, from about 0.07% w/w to about 2% w/w, from about 0.08%w/w to about 1% w/w, from about 0.09% w/w to about 0.5% w/w, or fromabout 0.1% w/w to about 0.25% w/w of Compound (A) relative to the totaldry weight of the pharmaceutical composition. For example, at about0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%,about 0.11%, about 0.12%, about 0.13%, about 0.14%, about 0.15%, about0.16%, about 0.17%, about 0.18%, about 0.19%, about 0.20%, about 0.3%,about 0.5%, about 1%, about 1.5%, about 2%, or about 2.5% w/w relativeto the total dry weight of the composition. Preferably, compound (A) ispresent from about 0.05% to about 0.25%, or from about 0.08% to about0.15% w/w relative to the total dry weight of the pharmaceuticalcomposition.

The at least one protic polar solvent comprises organic solvents, water,or mixtures thereof. Suitable, protic polar organic solvents can beselected from, for example, but not limited to, methanol, ethanol,isopropanol, n-propanol, n-butanol, sec-butanol, iso-butanol,tert-butanol, hexanol, nitromethane, or mixtures thereof. Preferably,the organic solvent is selected from the group consisting of methanol,ethanol, isopropanol, n-propanol, n-butanol, or mixtures thereof. Morepreferably, the protic polar solvent is water, ethanol, or mixturesthereof. Particularly, the organic solvent is ethanol. The optionally atleast one polar protic solvent is evaporated at a temperature of about20° C. to about 130° C. Preferably, the at least one polar proticsolvent is removed at a temperature of about 50° C. to about 110° C.More preferably, at a temperature of about 70° C. to about 100° C.

Another aspect of the present invention relates to a process forpreparing the pharmaceutical composition for oral administrationcomprising particles, as defined herein, said process comprising thesteps of:

(i) Mixing the (b) mixture comprising Compound (A)(2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof), with at least onebinder, as defined herein, and optionally with at least one polar proticsolvent, as defined herein; and

(ii) Adding said mixture (i) to the (a) inert substrate of theparticles, as defined herein; wherein said polar protic solvent, whenpresent, is removed at a temperature of about 20° C. to about 130° C.Preferably, the polar protic solvent is removed at a temperature ofabout 50° C. to about 110° C. More preferably, at a temperature of about70° C. to about 100° C.

Another aspect of the present invention relates to a process forpreparing the pharmaceutical composition for oral administrationcomprising particles, as defined herein, said process comprising thesteps of:

(i) Mixing the (b) mixture comprising Compound (A)(2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof), with at least onebinder, as defined herein, in the presence of an organic solvent, water,or mixture thereof, as defined herein; and

(ii) Adding said mixture (i) to the (a) inert substrate of theparticles, as defined herein.

Another aspect of the present invention relates to a process forpreparing the pharmaceutical composition for oral administration, asdefined herein, wherein the mixture of step (i) is dispersed onto the(a) inert substrate.

Yet another aspect of the present invention relates to a process forpreparing the pharmaceutical composition for oral administration, asdefined herein, wherein the (a) inert substrate is coated with themixture of step (i).

A further aspect of the present invention relates to a process forpreparing the pharmaceutical composition for oral administration, asdefined herein, said process further comprising the step of adding anouter (c) seal coating layer onto said particles.

The (c) seal coating layer, as defined herein, preventschemical-physical interactions between the particles and any otheractive or non-active substances that may be used in the preparation ofthe final dosage form.

Another aspect of the present invention relates to the process forpreparing the pharmaceutical composition for oral administrationcomprising particles, as defined herein, said process comprising, forexample, the steps of:

-   -   (i) Mixing the (b) mixture comprising Compound (A), with at        least one binder, preferably the binder is polyvinyl        pyrrolidone, in the presence of ethanol, to obtain a solution;    -   (ii) Adding the solution from step (i) to the (a) inert        substrate of the particles, preferably, the (a) inert substrate        is lactose or mannitol; and    -   (iii) Optionally adding an outer (c) seal coating layer onto        said particles, preferably, the (c) seal coating layer is        hypromellose (HPMC).

Another aspect the present invention provides for a process forpreparing a dispersible solution comprising mixing the (b) mixturecomprising2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof, and at least onebinder with an organic solvent, as defined herein. Preferably, theorganic solvent is ethanol.

Another aspect the present invention relates to a dispersible solutioncomprising2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid, or apharmaceutically acceptable salt thereof, and at least one binder, in anorganic solvent.

Another aspect of the present invention relates to the process forpreparing the pharmaceutical composition for oral administrationcomprising particles, as defined herein, said process comprising, forexample, the steps of:

-   -   (i) Mixing the (b) mixture comprising Compound (A), with at        least one binder, preferably the binder is polyvinyl        pyrrolidone, in the presence of water, to obtain a suspension;    -   (ii) Adding the suspension from step (i) to the (a) inert        substrate of the particles, preferably, the (a) inert substrate        comprises a material which is selected from the group consisting        of lactose, microcrystalline cellulose, mannitol, sucrose,        starch, granulated hydrophilic fumed silica, or mixtures        thereof; and    -   (iii) Optionally adding an outer (c) seal coated layer onto said        particles, preferably, and the (c) seal coated layer is        hypromellose (HPMC).

Another aspect of the present invention provides for a process forpreparing a suspension comprising mixing the (b) mixture comprising2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof, at least onebinder, with water, as defined herein.

Another aspect of the present invention relates to a solid dispersioncomprising2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof, and at least onebinder, in water, as defined herein.

Another aspect of the present invention also provides for a process, asdefined herein, comprising the step of further adding at least oneadditional active pharmaceutical ingredient.

Another aspect of the present invention provides for a process furthercomprising preparing the final dosage form by mixing the particles withat least one pharmaceutically acceptable excipient. The at least onepharmaceutically acceptable excipient can be selected, for example, fromthe group consisting of lactose, mannitol, microcrystalline cellulose,dicalcium phosphate, polyvinyl pyrrolidone, hydroxypropylmethylcellulose, croscarmellose sodium, crospovidone, sodium starchglycolate, colloidal silicon dioxide, magnesium stearate, sodium stearylfumarate, or mixtures thereof. Preferably, the excipient can be selectedfrom the group consisting of mannitol, croscarmellose sodium, colloidalsilicon dioxide, magnesium stearate, or mixtures thereof.

The pharmaceutical composition comprising Compound A either with orwithout a binder, an inert substrate, or other excipients is hereafterreferred to as Composition Comprising Compound A. In one embodiment,compound (A) or a pharmaceutically acceptable salt thereof is presentfrom about 0.05% to about 2.5%, from about 0.07% to about 2%, from about0.08% to about 1%, from about 0.09% to about 0.5%, or from about 0.1% toabout 0.25% w/w relative to the total weight of Particles ComprisingCompound A. For example, at about 0.05%, about 0.06%, about 0.07%, about0.08%, about 0.09%, about 0.1%, about 0.11%, about 0.12%, about 0.13%,about 0.14%, about 0.15%, about 0.16%, about 0.17%, about 0.18%, about0.19%, about 0.20%, about 0.3%, about 0.5%, about 1%, about 1.5%, about2%, or about 2.5% w/w relative to the total eight of ParticlesComprising Compound A. Preferably, compound (A) or a pharmaceuticallyacceptable salt thereof is present from about 0.05% to about 0.25%, orfrom about 0.08% to about 0.15% w/w relative to the total weight ofComposition Comprising Compound A.

Composition Comprising Compound B

The present disclosure provides a composition, such as a solidcomposition, comprising Compound B. The identity of Compound B is notparticularly limited. In some instances, Compound B itself is acombination of two or more active pharmaceutical ingredients. Compound Bcan be a solid or a liquid. Thus, Composition Comprising Compound B canbe a particle, a granule, a dispersion (solid or liquid), a tablet, amini-tablet, a bead, a pellet, a solution, or a mixture thereof.

Compound B may be selected from the following classes of activepharmaceutical ingredients: glucagon-like peptide 1 (GLP-1) receptoragonists (GLP-1RAs), dipeptidyl peptidase-4 (DPP4) inhibitors,peroxisome proliferator-activated receptor (PPARs) agonists, acetyl-CoAcarboxylase (ACC) inhibitors, thyroid hormone receptor β (TRβ) agonists,ketohexokinase (KHK) inhibitors, diacylglycerol Acyltransferase 2(DGAT2) inhibitors, sodium-glucose linked transporter (SGLT) inhibitors,anti-inflammatory agents (such as chemokine receptor 2/5 (CCR2/5)antagonists), and anti-fibrosis agents (such as Galectin-3 inhibitorsand Lysyl oxidase-like 2 (LOXL 2) inhibitors).

In addition to Compound B, the composition can have one or moreadditional ingredients. for example one or more binders, one or morefillers, one or more disintegrants, or one or more lubricants. Furtheradditional ingredients can also be present, although it should beunderstood that no particular additional ingredient is required.

The one or more binders are discussed in the context of CompositionComprising Compound A above.

The one or more fillers, when used, can include at least one of lactose,microcrystalline cellulose, calcium phosphate dibasic anhydrous, calciumphosphate dibasic dihydrate, calcium phosphate tribasic, cellulosepowder, magnesium carbonate, calcium sulfate, starch, talc, sucrose,dextrose, mannitol, hydroxypropylmethyl cellulose, hydroxypropylcellulose, carboxymethylcellulose, fructose, xylitol, sorbitol, andcombinations thereof.

The one or more disintegrants, when used, can include at least one ofcross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, and sodium starch glycolate. For example, the one or moredisintegrants can be cross-linked sodium carboxymethyl cellulose. Theweight ratio of the one or more disintegrants, such as cross-linkedsodium carboxymethyl cellulose, to Compound B is not particularlylimited. For example, the one or more disintegrants can be present in anamount of from about 2% to about 10%, such as about 4% to about 8%, orabout 6%, by weight of the composition.

The one or more lubricants, when used, can include at least one of talc,silica, stearin, magnesium stearate, or stearic acid. For example, theone or more lubricants can be magnesium stearate. The one or morelubricants can be present in an amount of from about 0.25% to about 5%,such as from about 0.75% to about 3%, or about 1.25%, by weight of thecomposition.

Further additional ingredients that can be used are listed in Remington:The Science and Practice of Pharmacy, which is hereby incorporated byreference in its entirety for all purposes.

The composition discussed above containing Compound B is referred to asComposition Comprising Compound B (containing Compound B with or withoutother excipients) hereafter.

Composition Comprising Compounds A and B

The current invention also provides a fixed dose combination containingCompounds A and B. As discussed above, the effective formulation of lowdoses of Compound A or a pharmaceutically acceptable salt thereof proveddifficult. The current invention overcomes the difficulties informulating a fixed dose combination composition containing bothCompounds A and B by utilizing each of Composition Comprising Compound Aand Composition Comprising Compound B as intermediates. The fixed dosecombination composition prior to the conversion to a final dosage formis referred to as Composition Comprising Compounds A and B hereafter.

The current invention provides compatible Composition ComprisingCompound A and Composition Comprising Compound B. The free combinationof the two allows Compound A and Compound B in a desired proportionaccording to the desired pharmaceutical and/or therapeutic effects. Thecompatibility allows ready preparation of unit dosage forms, ormultiple-dosage forms from Composition Comprising Compounds A and B.

As an example, Composition Comprising Compound A and CompositionComprising Compound B are combined (e.g. mixed or blended) in aproportion for a desired therapeutic effect. One or more of the binders,fillers, disintegrants, lubricants, and other additional ingredientsdiscussed above can also be admixed in the combining process. The methodof combining is not particularly limited.

Dosage Forms

The pharmaceutical composition comprising Composition ComprisingCompound (A) may be directly converted into final dosage forms.Alternatively, as discussed above in detail, Composition ComprisingCompound (A) may also be combined with Composition Comprising Compound Bto form Composition Comprising Compounds A and B which then is processedinto final dosage forms.

Another aspect the present invention provides for a process, as definedherein, wherein the final dosage form is encapsulated or tableted.

The pharmaceutical composition, as disclosed herein, is intended to beadministered orally to humans and animals in unit dosage forms, ormultiple-dosage forms, such as, for example, a capsule, a caplet, apowder, pellets, granules, a tablet, a mini-tablet, a sachet, a pouch,or a stick pack. The pharmaceutical composition may contain Compound (A)or also with Compound (B) as described above. Preferably, the unitdosage form, or multi-dosage form, for example, is a capsule, a tablet,a mini-tablet, a sachet, a pouch, or a stick pack. More preferably, thepharmaceutical composition is in the form of a capsule, or a tablet.This can be achieved by mixing the pharmaceutical composition, asdefined herein, with diluents, lubricants, binders, disintegrants,and/or absorbents, colorants, flavours and sweeteners.

Capsules comprising the particles or the compositions of the invention,as defined herein, can be prepared using techniques known in the art.Suitable capsules can be selected from a soft gelatin capsule, a hardshell capsule, a hard gelatin capsule, a plant-based shell capsule, ahypromellose (HPMC) based capsule, or mixtures thereof. Thepharmaceutical composition, as described herein, can be presented in ahard gelatin capsule, a soft gelatin capsule, a hard shell capsule, or ahard plant shell capsule, hypromellose (HPMC) capsule wherein thepharmaceutical composition is further mixed with an inert solid diluent,for example, calcium carbonate, calcium phosphate, or cellulose-basedexcipient. The hard gelatin capsules are made of two-piece outer gelatinshells referred to as the body and the cap. The shell may comprisevegetal or animal gelatin (e.g. pork, beef, or fish based gelatin),water, one or more plasticizers, and possibly some preservatives. Thecapsule may hold a dry mixture, in the form of a powder, very smallpellets, or particles, comprising a non-bile acid FXR agonist, such asCompound (A), at least one binder, and optionally excipients. The shellmay be transparent, opaque, coloured, or flavoured. The capsulescontaining the particles can be coated by techniques well known in theart with enteric- and/or gastric-resistant or delayed-release coatingmaterials, to achieve, for example, greater stability in thegastrointestinal tract, or to achieve the desired rate of release. Hardgelatin capsules of any size (e.g. size 000 to 5) can be prepared.

Tablet comprising the particles of the invention, as defined herein, canbe prepared using techniques known in the art. Suitable tablets maycontain the particles in admixture with non-toxic pharmaceutical, whichare suitable for the manufacture of tablets. These excipients are, forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose (e.g. lactose SD), mannitol (e.g. mannitol DC), magnesiumcarbonate, kaolin, cellulose (e.g. microcrystalline cellulose, powderedcellulose), calcium phosphate, or sodium phosphate; granulating anddisintegrating agents, for example, croscarmellose sodium, crospovidone,sodium starch glycolate, corn starch, or alginic acid; gliding agents,for example, fumed silica (e.g. Aerosil®, Aeroperl®); binding agents(e.g. for example, methyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, starch, gelatin, or acacia); and lubricating agents, forexample magnesium stearate, sodium stearyl fumarate, stearic acid ortalc. The mixture of the particles in admixture with non-toxicpharmaceutical can be mixed using numerous known methods, such as, forexample, mixing in a free-ball, or tumble blending. The mixture of theparticles in admixture with non-toxic pharmaceutical can be compressedinto a tablet using tableting techniques known in the art, such as, forexample, a single punch press, a double punch press, a rotary tabletpress, or a compaction on a roller compaction equipment. The compressionforce applied to form the tablet can be any suitable compression forcethat allows obtaining a tablet, for example, the compression applied canbe between 0.5 to 50 kN, preferably between 1 to 30 kN. The tablets canbe uncoated or coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, tablets can be coated with asuitable polymer or a conventional coating material to achieve, forexample, greater stability in the gastrointestinal tract, or to achievethe desired rate of release, for example the tablet can be coated withhypromellose (HPMC), magnesium stearate, polyethylene glycol (PEG),polyvinyl alcohol (PVA), Opadry®, Opadry II®, or mixtures thereof. Forexample, a time delay material such as glyceryl monostearate or glyceryldistearate can be employed. Tablets of any shape or size can beprepared, and they can be opaque, coloured, or flavoured.

A flow chart depicting the manufacturing process of the pharmaceuticalcomposition comprising Compound (A) is shown below in Scheme 1.

The inert substrate, such as lactose or mannitol, may be pre-treated toprovide a granule so that the particle size is in an acceptable range,for example. The pre-treatment may employ an adequate binder, forexample, HPMC and polyvinylpyrrolidone. The pre-treatment granulationcan be a dry or wet process. The API such as Compound A is then layeredonto the pre-treated inert substrate as described above.

The non-bile acid FXR agonist, such as Compound (A), alone or incombination with a second active pharmaceutical ingredient, as disclosedherein, are present in the pharmaceutical composition in an amountsufficient to exert a therapeutically useful effect in the absence ofundesirable side effects on the patient treated. Due to the high potencyof Compound (A), a low dose is preferable. Each unit dose contains apredetermined amount of the Compound (A), sufficient to produce thedesired therapeutic effect. Each unit dose as disclosed herein, aresuitable for human and animal subjects, are packaged individually andmay be administered in fractions or multiples thereof. A multiple-doseform is a plurality of identical unit-dosage forms packaged in a singlecontainer to be administered in segregated unit-dose form. Examples ofmultiple-dose forms include vials, blisters, or bottles.

In accordance with the present invention, Compound (A) or itspharmaceutically acceptable salt may be present in the pharmaceuticalcomposition for oral administration in a low amount. In one aspect ofthe present invention relates to a pharmaceutical composition for oraladministration wherein the final dosage form comprises Compound (A) orits pharmaceutically acceptable salt, in an amount of about 0.01 mg toabout 2 mg, about 0.03 mg to about 1.5 mg, about 0.05 mg to about 1 mg,or about 0.07 mg to about 0.09 mg. Preferably, the low amount of thenon-bile acid FXR agonist, such as Compound (A), is about 0.01 mg, orabout 0.02 mg, or about 0.03 mg, or about 0.04 mg, or about 0.05 mg, orabout 0.06 mg, or about 0.07 mg, or about 0.08 mg, or about 0.09 mg, orabout 0.1 mg, or about 0.12 mg, or about 0.14 mg, or about 0.15 mg, orabout 0.2 mg, or about 0.25 mg, or about 0.5 mg, or about 0.8 mg, orabout 1 mg, or about 1.2 mg, or about 1.4 mg, or about 1.5 mg, or about1.8 mg, or about 2 mg. More particularly, the amount is about 0.01 mg,or is about 0.03 mg, or is about 0.09 mg, or is about 0.1 mg, or isabout 0.12 mg, or is about 0.14 mg, or is about 0.25 mg, or is about 0.5mg, or is about 1 mg, or is about 1.5 mg, or the amount is about 2 mg.More preferably, the amount is about 0.01 mg, or is about 0.03 mg, or isabout 0.09 mg, or is about 0.1 mg, or is about 0.5 mg, or the amount isabout 2 mg.

A further aspect of the invention relates to a pharmaceuticalcomposition for oral administration, as defined herein, comprising atleast one further active pharmaceutical ingredient Compound (B) in atherapeutically effective amount.

Use

The pharmaceutical composition for oral administration, as disclosedherein, is useful, for example, as medicine, for the treatment of an FXRmediated condition or disorder such as, for example, cholestasis,intrahepatic cholestatis, estrogen-induced cholestasis, drug-inducedcholestasis, cholestasis of pregnancy, parenteral nutrition-associatedcholestasis, primary biliary cirrhosis (PBC), non-alcoholic fatty liverdisease (NAFLD), non-alcoholic steatohepatitis (NASH), liver cirrhosis,alcohol-induced cirrhosis, cystic fibrosis, or liver fibrosis.Specifically, the present disclosure provides the use of saidpharmaceutical composition in the treatment of primary biliary cirrhosis(PBS), or non-alcoholic steatohepatitis (NASH).

Accordingly, the final dosage form for oral administration, preparedfrom the pharmaceutical composition of the current invention, is useful,for example, as medicine, for the treatment of an FXR mediated conditionor disorder such as, for example, cholestasis, intrahepatic cholestatis,estrogen-induced cholestasis, drug-induced cholestasis, cholestasis ofpregnancy, parenteral nutrition-associated cholestasis, primary biliarycirrhosis (PBC), non-alcoholic fatty liver disease (NAFLD),non-alcoholic steatohepatitis (NASH), liver cirrhosis, alcohol-inducedcirrhosis, cystic fibrosis, or liver fibrosis. Specifically, the presentdisclosure provides the use of said pharmaceutical composition in thetreatment of primary biliary cirrhosis (PBS), or non-alcoholicsteatohepatitis (NASH).

Another aspect of the invention also provides for the use of thepharmaceutical composition, as disclosed herein, for the manufacture ofa medicament for cholestasis, intrahepatic cholestatis, estrogen-inducedcholestasis, drug-induced cholestasis, cholestasis of pregnancy,parenteral nutrition-associated cholestasis, primary biliary cirrhosis(PBC), non-alcoholic fatty liver disease (NAFLD), non-alcoholicsteatohepatitis (NASH), liver cirrhosis, alcohol-induced cirrhosis,cystic fibrosis, or liver fibrosis, preferably for primary biliarycirrhosis (PBS), or non-alcoholic steatohepatitis (NASH). Specifically,the present disclosure provides the use of said pharmaceuticalcomposition in the treatment of primary biliary cirrhosis (PBS), ornon-alcoholic steatohepatitis (NASH).

Another aspect of the invention also provides for a method of treating adisease or disorder in a patient in need thereof, wherein the disease ordisorder is cholestasis, intrahepatic cholestatis, estrogen-inducedcholestasis, drug-induced cholestasis, cholestasis of pregnancy,parenteral nutrition-associated cholestasis, primary biliary cirrhosis(PBC), non-alcoholic fatty liver disease (NAFLD), non-alcoholicsteatohepatitis (NASH), liver cirrhosis, alcohol-induced cirrhosis,cystic fibrosis, or liver fibrosis, comprising the step of administeringto the patient an effective amount of the pharmaceutical composition orthe final dosage form. Specifically, the present disclosure provides amethod of treating primary biliary cirrhosis (PBS), or non-alcoholicsteatohepatitis (NASH).

Definitions

The term “farnesoid X receptor” or “FXR” refers to all mammalian formsof such receptors including, for example, alternative splice isoformsand naturally occurring isoforms (Huber et al. Gene, 2002, 290, 35).Representative farsenoid X receptor species include, without limitation,the rat (GenBank Accession No. NM_021745), the mouse (GenBank AccessionNo. NM_009108), and the human (GenBank Accession No. NM_005123) forms ofthe receptor.

The term “non-bile acid FXR agonist” refers to an agent that directlybinds to and upregulates the activity of non-bile acid FXRs.Particularly, the term “agonist” refers to an agent that triggers atleast one response by binding a non-endogenous ligand to the receptor.The agonist may act directly or indirectly with a second agent thatitself modulates the activity of the receptor. The agonist may also actindirectly by modulating the activity of one or more agent(s) thatmodulate the amount of FXR mRNA or FXR protein in certain cells of apatient.

The term “pharmaceutically acceptable salts” refers to salts that can beformed, for example, as acid addition salts, preferably with organic orinorganic acids. For isolation or purification purposes it is alsopossible to use pharmaceutically unacceptable salts, for examplepicrates or perchlorates. For therapeutic use, only pharmaceuticallyacceptable salts or free compounds are employed (where applicable in theform of pharmaceutical preparations), and these are therefore preferred.The term “pharmaceutically acceptable” refers to those compounds,materials, compositions, and/or dosage forms which are suitable for usein contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, allergic response, other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

The term “treat”, treating” or “treatment” of any disease or disorderrefers to ameliorating the disease or disorder (e.g. slowing, arrestingor reducing the development of the disease, or at least one of theclinical symptoms thereof), to preventing, or delaying the onset, ordevelopment, or progression of the disease or disorder. In additionthose terms refer to alleviating or ameliorating at least one physicalparameter including those which may not be discernible by the patientand also to modulating the disease or disorder, either physically (e.g.stabilization of a discernible symptom), physiologically (e.g.stabilization of a physical parameter), or both.

The term “about”, as used herein, is intended to provide flexibility toa numerical range endpoint, providing that a given value may be “alittle above” or “a little below” the endpoint accounting for variationsone might see in the measurements taken among different instruments,samples, and sample preparations. The term usually means within 10%,preferably within 5%, and more preferably within 1% of a given value orrange.

The terms “pharmaceutical composition” or “formulation” can be usedherein interchangeably, and relate to a physical mixture containing atherapeutic compound to be administered to a mammal, e.g. a human, inorder to prevent, treat, or control a particular disease or conditionaffecting a mammal. The terms also encompass, for example, an intimatephysical mixture formed at high temperature and pressure.

The term “oral administration” represents any method of administrationin which a therapeutic compound can be administered through the oralroute by swallowing, chewing, or sucking an oral dosage form. Such oraldosage forms are traditionally intended to substantially release and/ordeliver the active agent in the gastrointestinal tract beyond the mouthand/or buccal cavity.

The term “a therapeutically effective amount” of a compound, as usedherein, refers to an amount that will elicit the biological or medicalresponse of a subject, for example, ameliorate symptoms, alleviateconditions, slow or delay disease progression, etc. The term “atherapeutically effective amount” also refers to an amount of thecompound that, when administered to a subject, is effective to at leastpartially alleviate and/or ameliorate a condition, a disorder, or adisease. The term “effective amount” means the amount of the subjectcompound that will engender a biological or medical response in a cell,tissue, organs, system, animal or human that is being sought by theresearcher, medical doctor or other clinician.

The term “comprising” is used herein in its open ended and non-limitingsense unless otherwise noted. In a more limited embodiment “comprising”can be replaced by “consisting of”, which is no longer open-ended. In amost limited version it can include only feature steps, or values aslisted in the respective embodiment.

The terms “low dose”, “low dosage strength”, or “low amount”, as usedherein, can be used interchangeably, and refer to a low amount of theactive pharmaceutical ingredient ranging from about 0.001 mg to about 10mg, preferably to an amount ranging from about 0.1 mg to about 2 mg.

The term “particle(s)”, as used herein, refers to a particle orparticles, comprising an (a) inert substrate, and (b) a mixturecomprising compound (A), and at least one binder. The inert substrate,as disclosed herein, together with the coating defines the size of theparticle. For example, the particle can have a size from about 20 μm toabout 500 μm. Preferably, the particle can have a size from about 50 μmto 400 μm. More preferably, the particle can have a size of about 100 μmto about 300 μm. The particle size is measured, for example, by by laserdiffraction methodology (e.g. particle size distribution (PSD)), usingthe equipment described herein.

The term “inert substrate”, as used herein, refers to a substance or amaterial that does not react with neither a chemically or biologicallyreactive substance, and will not decompose.

The term “binder”, is used herein in its established meaning in thefield of pharmaceutics. It refers to a non-active substance that isadded alongside the active pharmaceutical ingredient (herein referred toas Compound (A)), e.g. adhesion to the inert substrate particles in caseof compound (A) deposition or in case of tableting as a promoter ofcohesive compacts which enables to form granules and which ensures thatgranules can be formed with the required mechanical strength. Allbinders, referred herein, are used in qualities suitable forpharmaceutical use and are commercially available under various brandnames as indicated in the following examples:

-   -   Polyvinyl pyrrolidone (INN Ph. Eur.) is commercially available        under the trade name Povidone K30 or PVP K30 (approximate        molecular weight 50 000).    -   Shellac (INN Ph. Eur.) is a commercially available resin        excreted by the females of the insects Laccifer lacca Kerr,        Kerria lacca Kerr, Tachardia lacca, Coccus lacca and Carteria        lacca on various trees. Shellac composition is as follows: 46%        Aleuritic acid (HOCH₂(CH₂)₅CHOHCHOH(CH₂)₇COOH), 27% Shellolic        acid (a cyclic dihydroxy dicarboxylic acid and its homologues),        5% Kerrolic acid (CH₃(CH₂)₁₀(CHOH)₄COOH), 1% Butolic acid        (C₁₄H₂₈(OH)(COOH)), 2% Esters of wax alcohols and acids, 7%        Non-identified neutral substances (e.g. coloring substances,        etc), and 12% Non-identified polybasic esters.    -   Polyvinyl alcohol (INN Ph. Eur.) is commercially available under        the trade name Polyviol or PVA (approximate molecular weight 28        000 to 40 000).    -   Polyethylene glycol (Ph. Eur.) is commercially available under        the trade name PEG-n, where “n” is the number of ethylene oxide        units (EO-units) (approximate molecular weight up to 20 000).    -   Polyvinyl alcohol-polyethylene glycol co-polymer also known as        polyvinyl alcohol-PEG copolymer.

Abbreviations

% w/w Percent weight by weight

ALT alanine aminotransferase

API Active pharmaceutical ingredient

AV Acceptance value

BMI Body mass index

C4 7-hydroxy-4-cholesten-3-one

CAP Cellulose acetate phthalates

CAT Cellulose acetate trimellitates

CU Content uniformity

DAD Diode array detector

DSC Differential Scanning Calorimetry

FGF fibroblast growth factor

FXR Farsenoid X receptor

g/min Gram per minute

GGT gamma-glutamyl transferase

HCl Hydrochloric acid

HDL-C High-density lipoprotein cholesterol

HPMC Hypromellose/hydroxypropylmethyl cellulose

HPMCAS Hydroxypropyl methyl cellulose phthalates

INCI International Nomenclature of Cosmetic Ingredients

INN International nonproprietary name

Kg/g/mg/ng/μg Kilogram/Gram/Milligram/Nanogram/Microgram

kN Kilo Newton

LC (%) Percent of label claim

LDL-C low-density lipoprotein cholesterol

LFC liver fat content

LOS Loss on drying

m³/h Cubic meter per hour

mbar millibar

mL/L Milliliters/Liters

MRI-PDFF magnetic resonance imaging-proton density fat fraction

N Normal

NAFLD Non-alcoholic fatty liver disease

NASH Non-alcoholic steatohepatitis

° C. Degree Celsius

PBC Primary biliary cirrhosis

PEG Polyethylene glycol

Ph. Eur. European Pharmacopoeia (9^(th) edition)

PSD Particle Size Distribution

PVA Polyvinyl alcohol

PVAP Polyvinyl acetate phthalate

Q (%) Amount of active released

Q.S Quantity sufficient

RH Relative humidity

RSD Relative standard deviation

Sec/msec Seconds/milliseconds

SEM Scanning Electron Microscopy

TFA Trifluoroacetic acid

TG triglycerides

USP United States Pharmacoepia

UV Ultra Violet

w/v weight by volume

w/w weight by weight

XRPD X-ray Powder Diffraction

EXAMPLES

The following examples illustrate the invention and provide support forthe disclosure of the present invention without limiting the scope ofthe invention.

Analytical Details

-   -   Dissolution conditions: The dissolution analysis were performed        using a USP II (paddles) apparatus in a medium comprising 0.5%        w/v sodium lauryl sulfate in 0.1N HCl, at a temperature of        37.0±0.5° C. Analysis were performed in a 900 ml vessel or in a        500 ml vessel.    -   Assay and degradation: The analysis was performed using the        following Column: Agilent pursuit XRs 3 μm C18 150×3 mm, column        temperature 30° C.

Detection: UV or DAD

Gradient: Eluant A: 0.05% TFA in water/Eluant B: 0.05% acetonitrile

Time [min] % A (Eluent A) % B (Eluent B) 0.0 86 14 15.3 14 86 20.4 14 8620.5 0 100 24.0 0 100 24.1 86 14 30.0 86 14

-   -   Content uniformity: The content uniformity analysis was        performed using the following: Column: Kinetex XB-C18% 5 μm        150×4.6, column temperature 30° C.

Detection: UV or DAD

Eluant A: 0.05% TFA in water/Eluant B: 0.05% acetonitrile (no gradient).

-   -   XRPD: The X-Ray Powder Diffraction (XRPD) analysis was performed        using a Panalytical Xpert Pro diffractometer equipped with a Cu        X-ray tube and a Pixcel detector system, using a monochromatic        Cu(Kα)-radiation. About 20 mg of each material was analyzed at        ambient temperature in transmission mode held between low        density polyethylene films. The Instrument parameters are as        follows:

Sample prep Transmission foil Range: 3-40° 2θ degrees Step size: 0.013°Counting time: (Step time) ~90 s Run time: 20 min Incident Optics Sollerslits: 0.02 rad Mirror: Beam Cu W/Si focusing MPD Divergence slit: ½°Antiscatter slit: ½° NO Beam attenuator, Mask or Filter DiffractedOptics Detector: PIXcel Soller slits: Large 0.02 rad Antiscatter slit:AS slit 7.5 mm Pixcel

-   -   DSC: Differential Scanning Calorimetry (DSC) analysis was        carried out using a Perkin Elmer Jade DSC system. The sample was        weighed into an aluminum pan and a lid was crimped into        position. The sample was heated under a nitrogen environment        from about 30° C. to 300° C. using a heating rate of 10°        C./minute.    -   PSD: Particle size distribution was determined using the Malvern        Mastersizer 3000 (MS3000) equipped with an Aero S dry dispersion        unit and micro tray. The Instrument parameters are as follows:

Lens/measuring range: 0.01 μm-3500 μm

Analysis sensitivity: Normal

Calculation model: Mie (material refractive index: 1.540, absorption:0.01)

Particle type: Non-spherical mode

Obscuration filtering: Yes_Obscuration limits: 0.10-6.00%

Feed rate: 45%

Disperser pressure: 2.2 bar

Auto start measurement: yes_Background measurement: 20 seconds

-   -   Sample measurement: 10 seconds    -   Raman Spectrometry: The Raman spectrometry was recorded on a        Witec Alpha 300 confocal Raman imaging system using 633 nm and a        Laser Helium-Neon (HeNe) 35 mW. The Instrument parameters are as        follows:

Laser wavelength: 532

Laser intensity (mA): 22

Integration Time (s): 0.6

Objective lens: 40×/0.6 Korr

Grating value: 600

Optical resolution (μm): 1

Example 1: Preparation of Composition Comprising Compound (A) withoutthe Outer Seal Coating Layer

The composition is prepared by first dissolving the binder polyvinylpyrrolidone (povidone K30), Compound (A), as defined herein, in a polarprotic solvent as defined herein to provide an API solution. Saidprepared API solution is then sprayed onto an inert substrate, such aslactose or Aeroperl®, in a fluid bed dryer by top spray. The mixture isthen dried to remove the solvent to provide Composition comprisingCompound (A), in this case a particle. Tables 1, 1A, and 2 belowillustrate the composition of the particles.

TABLE 1 Preparation of Composition Comprising Compound (A) from anethanolic solution. Formulations 1 and 2 contain Compound (A) at 0.06%and 0.1% w/w (dry basis), respectively. Formulation 1 Formulation 2 (F1)(F2) Quantity per Quantity per Material Batch (g) Batch (g) Spray DriedLactose 2000 2000 API Solution Compound (A) 1.20 2.00 Polyvinylpyrrolidone 1.80 3.00 (Povidone K30) Ethanol* 597 995 Total 600 1000*The ethanol is then evaporated.

TABLE 1A Preparation of Composition Comprising Compound (A) from anethanolic solution. Formulations 1A and 2A each contains Compound (A) at0.15% w/w (dry basis). Formulation 1A Formulation 2A (F1A) (F2A)Quantity per Quantity per Material Batch (g) Batch (g) Spray DriedLactose 4155.75 Spray Dried Mannitol 4155.75 API Solution Compound (A)6.75 6.75 Polyvinyl pyrrolidone 337.50 337.50 (Povidone K30) Ethanol*4951.90 4951.90 Total 4500 4500 *The ethanol is then evaporated.

TABLE 2 Composition Comprising Compound (A) prepared form an aqueoussuspension containing Compound (A) at 2% w/w. Formulation 3 Formulation4 (F3) (F4) Quantity per Quantity per Material Batch (g) Batch (g) Inertsubstrate (96% w/w)** 9.6 192 Compound (A) (2% w/w) 0.20 4.00 Polyvinylpyrrolidone 0.20 4.00 (Povidone K30) (2% w/w) Water* Q.S Q.S Total 10200 *The water has been evaporated. Loss on drying (LOD) <2% postprocessing. **The Inert substrate can be Aeroperl ®.

Alternatively, the inert substrate, such as lactose or Aeroperl®, waspre-treated with an aqueous hydroxypropyl methylcellulose solution toachieve a granule size uniformity. Table 2A shows an example of treatingthe spray dried lactose with a 5% aqueous solution of HPMC. The granulesof such surface treated inert substrate was then layered with a solutionof Compound (A) at an appropriate concentration, and dried to achieve aloading level of 0.1% to 0.15% of Compound (A) w/w relative to the totaldr weight of the composition.

TABLE 2A Pre-treatment of spray dried lactose to provide granulatedlactose. Material Quantity per Batch (g) Spray Dried Lactose 4496.520HPMC solution (5% w/w) Hydroxy propyl methyl cellulose 112.411 Purifiedwater 2135.813 ¹Removed during manufacturing process.

The pre-treated (granulated) lactose was then coated with the APIaccording to Table 2B below to provide Composition Comprising Compound(A) at 0.1% w/w (dry basis).

TABLE 2B Composition Comprising Compound (A) at 0.1% w/w prepared fromgranulated lactose. Material Quantity per Batch (g) Granulated Lactose4200.004 API solution (1% w/w) Polyvinyl pyrrolidone 42.468 Compound (A)4.247 Ethanol¹ 4642.719 Dry weight 4246.719 ¹Removed duringmanufacturing process.

Example 2: Preparation of Composition Comprising Compound (A), with SealCoating

Composition Comprising Compound (A), prepared according to any of theformulation examples (F1, F2, F3 and F4) disclosed in Example 1, werethen seal coated.

For example, the seal coating was performed by spraying a 5% w/w aqueoussolution of HPMC onto the particles prepared following Formulation 2(F2) (see Table 1), to achieve a theoretical weight gain of 3%. TheFormulation 2 (F2) comprising an outer seal coating is referred toherein as Formulation F2s.

During spraying a visual inspection was performed every 30 minutes toensure no agglomeration was occurring during the process.

Example 3: Capsule Formulations

To assess the content uniformity of each batch, the sealed coatedparticles comprising Compound (A) (e.g. as disclosed in Example 2) wereencapsulated into size 1 capsules. The term “capsules” refer to hardgelatin capsules unless otherwise specified.

-   -   Capsules (C1) comprising 30 up of Compound (A): In order to        manufacture final dosage forms, such as capsules, containing 30        μg of Compound (A), 51.7 mg of the particles from Example 1        (Formulation 1 (F1)) was blended with 1% magnesium stearate and        filled into a capsule size 1. The total weight of Compound (A)        (drug load) was 0.058% of the capsule. The fill weight was        adjusted accordingly.    -   Capsules (C2) comprising 160 μg of Compound (A): In the same        manner, the final dosage forms, such as capsules, containing 160        μg dose of Compound (A), were manufactured using 166.7 mg of the        particles from Example 1 (Formulation 2 (F2)) blended with 1%        magnesium stearate and filled into a capsule size 1. The total        weight of Compound (A) (drug load) was 0.096% of the capsule.        The fill weight was adjusted accordingly.

Based on the final compositions and process parameters established fromthe examples outlined above, confirmatory capsule batches weremanufactured using the same conditions for stability evaluation. Assaytesting was performed separately on:

-   -   Particles comprising Compound (A) without the seal coating layer        (F1 and F2)    -   Particles comprising Compound (A) and a seal coat (F1s and F2s)

Encapsulation was performed using the MG2 Labby encapsulation machine.Capsules were packaged in 30 count bottles for the stability study. Theresults from the confirmatory batches, including the content uniformity(CU) results, are shown in Table 3 and Table 4 below:

TABLE 3 Content uniformity results for the 30 μg capsule (C1) batch F1 +outer seal Formulation 1 (F1) coating (=F1 s) Sample % w/w % LC % w/w %LC 1 0.0576 96.1 0.0552 95.2 2 0.0586 97.7 0.0566 97.5 3 0.0615 102.40.0544 93.8 4 0.0559 93.2 0.0534 92.0 5 0.0535 89.1 0.0529 91.2 6 0.058196.9 0.0536 92.3 Mean 0.0580 95.9 0.054 93.7 % RSD 4.7 4.7 2.5 2.5Filter 0.0571 95.1 0.1008 173.7 Blend filled Capsule C1 (=F1 + outerseal coating) Sample % LC 1 94.1 2 94.7 3 97.0 4 94.3 5 93.9 6 95.3 796.9 8 95.8 9 96.7 10 96.4 Mean 95.5 % RSD 1.2 AV 5.8

TABLE 4 Content uniformity results for the 160 μg capsule (C2) batchF2 + outer seal Formulation 2 (F2) coating (=F2 s) Sample % w/w % LC %w/w % LC 1 0.0870 87.0 0.0967 99.6 2 0.0942 94.2 0.0947 97.5 3 0.096996.9 0.1040 107.1 4 0.0958 95.8 0.0924 95.2 5 0.0915 91.5 0.0927 95.5 60.0879 87.9 0.0907 93.4 Mean 0.092 92.2 0.095 98.1 % RSD 4.5 4.5 5.0 5.0Filter 0.1066 106.6 0.1645 169.4 Blend filled Capsule C2 (=F2 + outerseal coating) Sample % LC 1 97.7 2 98.5 3 98.0 4 98.3 5 97.6 6 98.1 797.7 8 97.4 9 97.5 10 98.8 Mean 97.9 % RSD 0.5 AV 1.7

As it can be seen in Table 3 and Table 4, the content uniformity resultsare well in the acceptable range for both the 30 μg and 160 μg dosestrengths of the filled capsules. This proves a scale-able andcommercially viable process was developed. In addition, both capsulestrengths (C1 and C2) were tested for stability up to 12 weeks and werefound to be stable with no apparent trends of change at 40° C./75% RHfor both physical (dissolution) and chemical integrity.

Dissolution performance was evaluated to ensure that the dissolutionprofile matched that of the dry blend formulation (Compound (A),lactose, crospovidone, magnesium stearate) in a capsule. The dissolutionrate is measured by the conventional method. In FIGS. 1 and 2, thedissolution rate (%) of C1, C2 and a capsule containing a dry blendcomprising 0.1 mg of Compound (A) is plotted over a course of 120 min.As can be seen in FIG. 1 and FIG. 2, both dose strengths yieldeddissolution greater than two times that of the dry blend formulation at15 minutes time point. Thus, the capsule formulation of thepharmaceutical composition has the advantage to provide a formulationwith fast dissolution rate, which is about 80% or more, in 20 minutes orless. This dissolution rate would meet the specification for animmediate release formulation whose dissolution rate is represented by“Q+5% Provisional.”

Example 4: Tablet Formulation and Stability Data

Tablet dosage forms were developed using the Formulation 2 with a sealcoating layer (F2s), as disclosed above in Example 2 and Example 3.Preliminary investigations to identify scalable and commercially viabletablet formulations indicated that a direct compression process wasfeasible. Two formulations were evaluated using a common blend approachand to cover the wide dose range mentioned herein. The compressionprofiles for both compositions were almost identical as outlined in thebelow examples.

TABLE 5 Tablet formulations Formulation 5 (F5) Formulation 6 (F6) mg/mg/ mg/ mg/ tablet tablet tablet tablet Material % 30 μg 160 μg g/batch% 30 μg 160 μg g/batch Formulation 2 51.54 30.93 164.95 154.64 51.5430.93 164.95 154.64 sealed coated (F2 s)* Drug Load 0.05 0.03 0.16 0.050.03 0.16 Compound (A) Lactose SD 28.45 17.07 91.05 85.36 15 9 48 45Mannitol DC 15 9 48 45 28.45 17.07 91.05 85.36 Croscarmellose 3 1.809.60 9 3 1.80 9.60 9 Sodium (Ac-Di-Sol) Aerosil 1 0.60 3.20 3 1 0.603.20 3 Magnesium 1 0.60 3.20 3 1 0.60 3.20 3 Stearate Total 100 60 320300 100 60 320 300 *Drug load Compound A = 0.097%

Formulation 6 at both dose strengths was manufactured in a larger scaleand was film coated using standard Opadry® brown film coat. Opadry® is acomplete film coating system made by Colorcon and it is Colorcon'scustomized one-step system that combines polymer, plasticizer andpigment in a dry concentrate. The analytical results from these batchesare disclosed in Table 6 (below), and are depicted in FIG. 3, and FIG.4.

TABLE 6 Dissolution and content uniformity results of the film coatedtablet Compound (A) 30 μg Compound (A) 160 μg film coated tablets filmcoated tablets Test Specification Tablet 1 (T1) Tablet 2 (T2) Assay90.0-110.0% of Label Claim (LC) 104.28% 104.10% Time Point DissolutionAs per USP <711> 15 min 102 100 and Ph. Eur. 2.9.3 30 min 104 103 (Q =70%) after 90 45 min 104 103 minutes 60 min 104 103 75 min 104 103 90min 104 103 120 min  104 103 Content Uniformity (CU) Preparation ContentUniformity of 1 104.52 105.21 Uniformity Dosage Units (by 2 103.97103.99 Content Uniformity) 3 103.46 101.64 must comply with 4 101.71102.90 Eur. Ph. 2.9.40 5 102.76 101.60 Acceptance Value 6 103.30 102.22(AV) less than or 7 101.72 102.80 equal to 15.0 8 103.07 101.89 9 103.41103.24 10  102.49 101.30 Mean 103.0 102.7 RSD % 0.8 1.2 AV 3.7 4.1

Dissolution performance was evaluated to ensure that the dissolutionprofile matched that of the dry blend formulation (Compound (A)encapsulated in a capsule, same as in Example 3). The dissolution rateis measured by the conventional method. FIG. 3 and FIG. 4 summarize thedissolution profiles of the tablets comprising the above formulations(Formulation 5 and Formulation 6), compressed at different compressionforces (2KN and 11 KN). The fast dissolution observed for the capsuleformulation (see FIG. 1 and FIG. 2) was not impacted by the compressionof the blend into tablets. Surprisingly, the dissolution rate observedwith the tablet formulations is even faster than the dissolution rate ofthe capsule formulations. As it can be seen in FIG. 3 and FIG. 4, thetablet formulations have the advantage to provide a formulation with adissolution rate of about 85% or more, in 20 minutes or less.

Both strengths (30 μg and 160 μg) made using Formulation 6 werefilm-coated and stability assays were performed on the correspondingfilm-coated tablets (Tablet 1 (T1) and Tablet 2 (T2) as seen in Table6). The results are depicted in Table 7 and Table 8 below.

TABLE 7 Assay stability data of Tablet 1 (T1) Time (weeks) 0 3 6 24 40°C./75% RH 104.3% 103.6% 104.6% 103.9% Dissolution*  104%  105%  106% 103% *As per (USP<711> and Ph. Eur. 2.9.3) Q = 70% after 90 minutes

TABLE 8 Assay stability data of Tablet 2 (T2) Time (weeks) 0 3 6 24 40°C./75% RH 104.1% 103.5% 105.2% 105.3% Dissolution*  103%  103%  103% 102% *As per (USP<711> and Ph. Eur. 2.9.3) Q = 70% after 90 minutes

After 24 weeks, the stability results, as shown in Table 7 and Table 8,confirm the stability of the drug product and no degradation isobserved. As can be seen in Table 7 and Table 8, the dissolutionperformance of the film-coated tablet is not compromised even underthese conditions.

Example 5: DSC, PSD, XRPD, SEM Analysis and Raman Spectroscopy

Differential Scanning Calorimetry (DSC), Particle Size Distribution(PSD) and X-ray Powder Diffraction (XRPD), Scanning Electron Microscopy(SEM) analysis, and Raman spectrometry were carried out on the materialsused for the development of the tablet formulations comprising Compound(A), as depicted in Formulation 5 and Formulation 6. These experimentshelped to characterize and determine the physical nature of Compound(A).

FIG. 5 shows the XRPD diffractograms for the lactose (commerciallyavailable—spray dried grade) as inert substrate, the seal coatedFormulation 2 (referred herein as F2s), and the common blend preparedaccording to Table 5, Formulation 6. Comparing all peaks together, theadditional peaks present in the diffractogram of the final blend can beattributed to Mannitol DC (˜11.5, 14.6, 16.8, 18.8, 20.5, 21.1, 21.7,23.4, 25.9, 26.1, 29.5, 30.6, 33.6, 33.7, 33.9, and 36.1° (20 degrees).

FIG. 6 shows the DSC thermogram used to determine the thermal profile ofthe sealed coated Formulation 2 (F2s) from about 30° C. to 300° C. at10° C./minute. The thermogram shows two distinct endotherms, which maybe attributable to melting of multiple components. The first endotherm(onset temperature about 134° C.) is broad, exhibiting both peakfronting and tailing, suggesting at least 3 components are present.Decomposition is evident towards the end of the second endotherm atabout 240° C. The thermal data generated for the sample is reported inTable 9 below.

TABLE 9 DSC thermal data obtained for the sealed coated formulation F2(F2 s) Endotherm 1 (° C.) Endotherm 2 (° C.) Sample Onset Heat PeakOnset Heat Peak Descrip- Temp. Flow Temp. Temp. Flow Temp. tion (° C.)(J/g) (° C.) (° C.) (J/g) (° C.) F2 s 134.48 140.5300 140.60 209.99278.2691 218.56

FIG. 7 and FIG. 8 show particle size distribution of the seal coatedFormulation 2 (F2s) and the Formulation 6 (F6), which were determined bylaser diffraction using dry dispersion. Particle size analysis for eachsample was performed in triplicate. The mean particle size datadetermined for the Dv10, Dv50 and Dv90 are reported in Table 10 below:

TABLE 10 Particle size data determined for the particle made accordingto the Formulation 2 (F2) and the Formulation 6 μm Material Prep# Dv10Dv50 Dv90 Seal Coated 1 115.669 173.540 254.715 Formulation 2 2 117.853169.732 241.322 (F2 s) 3 120.457 173.614 248.519 Mean 117.99 172.30248.19 % RSD 2 1 3 Formulation 6 1 60.253 153.844 261.210 (F6) 2 67.160152.807 255.700 3 66.476 151.540 257.340 Mean 64.63 152.73 258.08 % RSD6 1 1

The XRPD and DSC results alone were unable to distinguish the physicalnature of Compound (A) due to the extremely low drug concentration of0.1% and the presence of other excipients especially in the blend usedfor the tablet dosage form. In view of this, additional investigationswere conducted, such as SEM analysis.

The SEM analysis was performed on the following samples:

-   -   Lactose (commercially available—spray dried grade)    -   Formulation 2, as disclosed herein    -   Seal Coated Formulation 2 (F2s)

SEM images of each of the above batches are shown in FIGS. 9 to 14. InFIG. 10, crystals of Compound (A) are visible relative to FIG. 9, theLactose without Compound (A), FIGS. 11 to 14 show the appearance of theFormulation 2 (F2) and the seal coated Formulation F2 (F2s), asdisclosed herein, at two different resolutions. The seal coatedparticles of the Formulation 2 (F2s) have a smooth surface compared tothe particles of the Formulation 2 (F2) without the seal coating layer.This demonstrates that the seal coating was effective.

To confirm the crystalline nature of the drug, Raman microscopy andanalysis were investigated to determine the spatial distribution on the(a) inert substrate, in this case lactose. This study aimed atdetermining the spatial distribution of compound (A), in the Formulation2 (F2), once dispersed onto the inert substrate (drug load of 0.1% andPVPK30 as binder). A suitable amount of particles were deposited onto amicroscopy slide and a single surface Raman mappings (150×150 μm²-1 μmresolution/0.6 s second integration time) was performed.

Scanning the sample surface and mapping Raman spectra across the scannedarea showed clearly defined (microparticle-like) areas where spectracould be associated with crystalline Compound (A), while in-betweenthose areas the Raman spectra were associated with excipients (binder,carrier) only (as seen in FIG. 15 and FIG. 16).

Samples of crystalline Compound (A) and amorphous Compound (A) wereprepared from pure compound (A), and were used as a comparisonReference.

-   -   The crystalline Compound (A) was prepared according to well        known in the art crystallisation technique.    -   Amorphous Compound (A) was prepared as followed: 30 mg of        Compound (A) was dissolved in 1.5 mL of dioxane in 2 separate        vials. The vials were shock frozen in dry ice. Lyophilisation        was performed overnight, using techniques well known in the art,        until amorphous Compound (A) was obtained. The amorphous sample        was analysed using XRPD/DSC.

Those samples were analysed by Raman spectroscopy (see FIG. 17, socalled “Compound (A) crystalline reference” and “Compound (A) amorphousreference”). Raman spectra of reference crystalline Compound (A) andamorphous Compound (A) were compared to that of Compound (A) extractedfrom the Formulation 2 (F2). As seen in FIG. 17, Compound (A) layeredonto the inert substrate (e.g lactose), according to the Formulation 2(F2), exhibits clear correlation with the Raman fingerprint of “Compound(A) crystalline reference” in terms of characteristic Raman peakpositions. Thus, showing that Compound (A) can also be present in acrystalline form in the pharmaceutical composition.

Example 6: Compound (A) for the Treatment of NonalcoholicSteatohepatitis—Interim Results Based on Baseline Body Mass Index fromPhase 2b Study FLIGHT-FXR

The FLIGHT-FXR (NCT02855164) is a Phase 2, randomized, double-blind,multicenter, placebo-controlled trial with an adaptive design to assessthe safety, tolerability, and efficacy of Compound (A) in patients withNASH (nonalcoholic steatohepatitis). Data from Compound (A) 60 μg,Compound (A) 90 μg, and placebo arms are provided herein-below.

Patients were divided into two subgroups: Lower BMI subgroup (BMI <30kg/m² (Asian) or <35 kg/m² (Non-Asian)) and Higher BMI subgroup (BMI ≥30kg/m² (Asian) or >35 kg/m² (Non-Asian))

The objectives of the study were as follows:

-   -   To determine the dose-response relationship of compound (A) on a        marker of FXR target engagement in the gut (FGF19) by BMI        subgroups over time.    -   To determine dose-response relationship of compound (A) on        markers of hepatic inflammation (alanine aminotransferase        [ALT]), target engagement and marker of oxidative stress        (gamma-glutamyl transferase [GGT]), and on changes in liver fat        content (LFC) measured by magnetic resonance imaging proton        density fat fraction (MRI-PDFF) at Week 12 by BMI subgroups.    -   To determine lipids profile by BMI subgroups.

TABLE 11 Study population Key inclusion criteria Key exclusion criteriaMale and female patients aged ≥18 years, History of livertransplantation weighing ≥40 and ≤150 kg Liver fat content ≥10% atscreening Uncontrolled diabetes mellitus (DM) defined as HbA1c ≥9.5%within 60 days prior to enrolment Presence of NASH was defined by: Priordiagnosis of other forms of chronic liver Liver biopsy consistent withNASH and disease, presence of cirrhosis on liver biopsy, fibrosis levelF1, F2, or F3, obtained 2 years or clinical diagnosis of cirrhosisand/or platelet or less prior to randomisation, no diagnosis of count<120 × 109/L or severe liver impairment alternate chronic liver diseaseand elevated Current or history of significant alcohol ALT (≥43 IU/L[males] or ≥28 IU/L [females]) consumption (male, >30 g/day; female, >20OR g/day, on average) for a period of >3 consecutive months within 1year prior to Phenotypic diagnosis based on all of the screening and/ora score on the AUDIT following: elevated ALT (≥43 IU/L [males]questionnaire ≥8 or ≥28 IU/L [females]), BMI ≥27 kg/m² (in Pregnant ornursing patients with a self-identified race other than (lactating)mothers Asian) or ≥23 kg/m² (in patients with a self- Previous exposureto obeticholic acid identified Asian race), and diagnosis of Type 2diabetes mellitus (DM) by having either glycocylated haemoglobin (HbA1c)≥6.5% or drug therapy for Type 2 DM

Results and Efficacy of 60 μg Compound (A), 90 μg Compound (A), andPlacebo

Table 12 (below) shows the results observed in each treatment arms.

TABLE 12 Geometric mean percentage change in markers of efficacy (FGF19(4 hours post-dose from pre-dose at Week 6) and all others parametersfrom baseline to Week 12)) by BMI subgroups (with N, total number ofpatients) Lower BMI^(†) Higher BMI^(‡) Compound (A), Compound (A),Compound (A), Compound (A), Placebo 60 μg 90 μg, Placebo 60 μg 90 μgParameters, % N = 28 N = 21 N = 52 N = 18 N = 16 N = 33 FGF19 21.5 360.2585.8 68.0 276.9 446.9 C4 2.8 −33.2 −40.4 37.3 −48.9 −61.8 GGT −10.8−47.0 −61.3 −6.8 −38.4 −48.7 ALT −18.6 −26.0 −26.8 −10.6 −14.8 −19.5LFC^(§) −13.1 −19.9 −18.8 −5.5 −12.9 −11.4 HDL-C −4.8 −1.9 −7.7 −3.9−6.1 −11.9 TG 1.2 0.9 5.7 0.9 −6.7 −2.3 ^(†)BMI < 30 kg/m² (Asian) or<35 kg/m² (Non-Asian); ^(‡)BMI ≥ 30 kg/m² (Asian) or ≥35 kg/m²(Non-Asian); ^(§)Measured by MRI-PDFF

-   -   Effect of Compound (A) on marker of target engagement: FGF19:        the assessment of FGF19 was done at Week 6. A dose-response        increase in the FGF19 levels was observed 4 hours post-dose        compared with pre-dose in both BMI subgroups. At Week 6, the        geometric mean percentage changes in FGF19 from pre-dose in the        lower BMI subgroup (60 μg of Compound (A)=360.2, and 90 μg of        Compound (A)=585.8) were higher than the mean percentage changes        in the higher BMI subgroup (60 μg of Compound (A)=276.9, and 90        μg of Compound (A)=446.9).    -   Effect of Compound (A) on marker of hepatic inflammation: ALT: A        rapid and sustained decline in ALT levels from baseline was        observed with 90 μg of Compound (A) doses in patients from both        BMI subgroups, more marked in the group with lower BMI.    -   Effect of Compound (A) on GGT, a marker of oxidative stress: A        dose-response decrease in GGT levels was observed with        Compound (A) in both BMI subgroups, more marked in the group        with lower BMI. At Week 12, the geometric mean percentage change        in GGT was higher with 60 μg of Compound (A) (−47.0) and 90 μg        of Compound (A) (−61.3) in the lower BMI versus 60 μg of        Compound (A) (−38.4) and 90 μg of Compound (A) (−48.7) in the        higher BMI subgroup.    -   Effect of Compound (A) on liver fat content: At Week 12, the        mean percentage change was greater in all arms in the lower BMI        subgroup (placebo=−13.1; Compound (A) 60 μg=−19.9, and        Compound (A) 90 μg=−18.8) compared with the higher BMI subgroup        (placebo=−5.5; Compound (A) 60 μg=−12.9, and Compound (A) 90        μg=−11.4). The proportion of patients with an absolute decrease        of Liver fat content (LFC) by >5% was higher in the lower BMI        subgroup versus the higher BMI subgroup.    -   Effect of Compound (A) on C4: At Week 12, a decrease of        7-hydroxy-4-cholesten-3-one (C4) was observed in all        Compound (A) treatment groups. This decrease is more obvious in        the higher BMI subgroup. However, C4 is subject to diurnal        variation, therefore, the influence of BMI on C4 invites further        investigation.

As far as the safety of the formulation comprising Compound (A) isconcerned, the Incidence of adverse events, including pruritus, wascomparable between arms. Lipid profiles were comparable in both BMIsubgroups. The interim results from the first two parts of this Phase 2bstudy provide the evidence for target engagement, anti-inflammatory, andantisteatotic effects of Compound (A) in both BMI subgroups. However,the effect of Compound (A) on ALT, GGT, and LFC was more pronounced inthe lower BMI subgroup. The study also showed that the lipid profileswere comparable in both subgroups and that rates of events in the study,including pruritus, were comparable across treatment arms. Consistenttrends of lower responses in the higher BMI subgroup, receiving lowerdosing by body weight, support testing higher Compound (A) doses (e.g.140 and 200 μg/day).

Example 7: Absorption, Distribution, Metabolism, and Excretion ofCompound (A), Following a Single 1-Mg Oral Dose of [¹⁴C] Compound (A) inHealthy Human Subjects

Absorption, distribution, metabolism, and excretion of Compound (A) wasstudied following a single 1-mg oral dose of [¹⁴C]Compound (A) to fourhealthy human subjects. The rate and route of excretion of [¹⁴C]Compound(A) related radioactivity was determined as well as pharmacokineticprofiles of Compound (A) and of total radioactivity in plasma. The keybiotransformation pathways and clearance mechanisms of [¹⁴C]Compound (A)in human were elucidated. Mass balance was achieved with approximately94% of the administered dose recovered in excreta through the 312 hourscollection period. Faecal excretion of Compound (A) relatedradioactivity played a major role (approximatively 65% of the totaldose) while urinary excretion played a slightly minor role(approximatively 29% of the total dose). After oral administration of 1mg [¹⁴C]Compound (A) to human subjects, parent Compound (A) reached amaximum concentration (Cmax) of 33.5 ng/mL with a median Tmax (time themaximum concentration is reached) of 4 hours and eliminated with a halftime (t^(1/2)) of 13.5 hours in plasma. Unchanged Compound (A) was theprincipal drug-related component found in the plasma (approximatively92% of total radioactivity). Two minor oxidative metabolites, wereobserved in circulation, at approximatively 2% and approximatively 5% ofthe total drug radioactivity exposure, respectively. Compound (A) waseliminated predominantly via metabolism with more than 68% of the doserecovered as metabolites in excreta. Oxidative metabolism appeared to bethe major clearance pathway of Compound (A) as the majority of theradioactivity observed in human excreta consisted of oxidativemetabolites. Primary phase 1 oxidative pathways included: 1) oxidativeO-dealkylation; 2) oxidation at the phenylcyclopropyl isoxazole moiety;3) oxidation at the benzothiazole and fused ring structure. Metabolitescontaining multiple oxidative modifications and/or glucuronidation tooxidative products were also observed in human excreta.

Example 8: In Vivo PK

The PK profiles of the Compound (A) drug products were evaluated in malebeagle dogs according to the following method:

Drug substance: Compound (A);

Drug products: S1—hard gelatin capsules, S2—soft gelatin capsules, andS3—film coated tablets according to the compositions below:

mg/unit S1 Compound (A) 0.03 Lactose 28.92 Crospovidone 0.9 Magnesiumstearate 0.15 Capsule 48 S2 Compound (A) 0.03 Propylene glycolmonolaurate 139.97 Glycerol 35.64 Gelatin 67.49 Purified water 48.53Titanium dioxide 1.52 Glycerol 1.52 Purified water 0.3 S3 Formulation 230.09 (30 μg Compound (A)) Lactose 9 Mannitol 17.1 Croscarmellose Sodium1.8 Silicon dioxide 0.6 Magnesium stearate 0.6 HPMC Coating 5

Species, strain, sex: beagle dog, male (n=4), crossover;

Route of administration: Oral (pentagastrin pre-treatment (6 μg/kg i.m.)30 min prior to dosing);

Feeding status: Fasted overnight prior to dose administration. Food wasreturned to the animals after 4 h sample collection;

Dose: 30 μg/animal/dose;

Sample collected: K₂-EDTA Blood (plasma analyzed);

Sampling time points: 0.25, 0.5, 1, 2, 3, 5, 8, 24, 28 and 32 h postdose;

Sample analysis: LC-MS/MS with positive electrospray ionization.

The PK results are summarized in Table 13 below.

TABLE 13 PK properties of certain embodiments of the invention DrugProduct S1 S2 S3 Dose  0.00313 ± 0.000439  0.00313 ± 0.000445  0.00315 ±0.000470 Tmax^(a) (h) 3.0 [2-24]   3.0 [2-8]   3.0 [2-5]   Tlast^(a) (h)32 [32-32] 32 [32-32] 32 [32-32] Cmax (ng/mL)  1.71 ± 0.740  2.89 ±0.871  3.37 ± 0.974 Cmax/dose 57.0 ± 24.7 96.4 ± 29.0  112 ± 32.5(ng/mL)/(mg) AUClast (h*ng/mL) 24.1 ± 6.65 43.9 ± 6.71 36.2 ± 5.60AUClast/dose 802 ± 222 1460 ± 224  1210 ± 187  (hr*ng/mL/mg) AUCinf(h*ng/mL) 27.5 ± 7.60 46.7 ± 7.64 41.6 ± 4.56 AUCinf/dose 916 ± 253 1560± 255  1390 ± 152  (h*ng/mL)/(mg) Bioavailability (%) 100  192 ± 49.8 157 ± 38.6 ^(a)Median [range].

The average plasma concentration profile of the three examples aregraphed in FIG. 18. As shown in Examples 3 and 4, the current inventionprovides a composition with a superior in vitro dissolution profile ofCompound (A) relative to the dry blend composition. The superiordissolution is manifested in the higher bioavailability in vivo in thedog as demonstrated here.

1. A pharmaceutical composition for oral administration comprising (a)an inert substrate, and (b) a mixture comprising2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof, and at least onebinder.
 2. The pharmaceutical composition of claim 1, wherein2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid is in a free form.
 3. The pharmaceutical composition of claim 1,wherein the (a) inert substrate comprises a material selected from thegroup consisting of lactose, microcrystalline cellulose, mannitol,sucrose, starch, granulated hydrophilic fumed silica, or mixturesthereof.
 4. The pharmaceutical composition of claim 1, wherein thebinder is selected from the group consisting of polyvinyl pyrrolidone,hydroxypropyl cellulose, hypromellose, carboxymethyl cellulose, methylcellulose, hydroxyethyl cellulose, carboxyethyl cellulose,carboxymethylhydroxyethyl cellulose, polyethylene glycol,polyvinylalcohol, shellac, polyvinyl alcohol-polyethylene glycolco-polymer, or a mixtures thereof.
 5. The pharmaceutical composition ofclaim 1, wherein the pharmaceutical composition is a particle.
 6. Thepharmaceutical composition according to claim 5, wherein the particlefurther comprises an outer (c) seal coating layer.
 7. The pharmaceuticalcomposition according to claim 6, wherein the outer (c) seal coatinglayer is selected from the group consisting of hydroxypropyl methylcellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, carboxymethylcellulose, methyl cellulose, hydroxyethyl cellulose, carboxyethylcellulose, carboxymethylhydroxyethyl cellulose, polyethylene glycol,polyvinylalcohol, or mixtures thereof.
 8. The pharmaceutical compositionaccording to claim 1, comprising at least one further activepharmaceutical ingredient.
 9. A final dosage form comprising thepharmaceutical composition according to claim 1, wherein the finaldosage form is a capsule, a tablet, a mini-tablet, a sachet, or astickpack.
 10. The final dosage form according to claim 9, wherein thefinal dosage form is a capsule or a tablet.
 11. The final dosage formaccording to claim 9, comprising2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof, in an amount ofabout 0.01 mg to about 2 mg.
 12. A process for preparing apharmaceutical composition for oral administration comprising (a) aninert substrate, and (b) a mixture comprising2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof, and at least onebinder, the process comprising the steps of: (i) mixing the2-[(1R,3r,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylicacid, or a pharmaceutically acceptable salt thereof, with the at leastone binder to form the mixture; and (ii) adding the mixture of step (i)to the inert substrate.
 13. The process of claim 12, wherein step (i)comprises mixing further with at least one protic polar solvent, whereinthe process further comprising the step of: (iii) removing the at leastone protic polar solvent.
 14. The process of claim 13, wherein the atleast one protic polar solvent is selected from the group consisting oforganic solvents, water, or mixtures thereof.
 15. The process of claim14, wherein the organic solvent is selected from the group consisting ofmethanol, ethanol, isopropanol, n-propanol, n-butanol, or mixturesthereof.
 16. The process of claim 12, wherein in step (ii) adding themixture of step (i) to the inert substrate comprises dispersing themixture of step (i) onto the (a) inert substrate.
 17. The process ofclaim 12, wherein in step (ii) adding the mixture of step (i) to theinert substrate comprises coating the (a) inert substrate with themixture of step (i).
 18. The process of claim 12, wherein thepharmaceutical composition is a particle, and wherein the processfurther comprises the step of adding an outer (c) seal coating layeronto said particle.
 19. The process according to claim 12, furthercomprising the step of adding at least one additional activepharmaceutical ingredient.
 20. A method of treating a disease ordisorder in a patient in need thereof, wherein the disease or disorderis cholestasis, intrahepatic cholestatis, estrogen-induced cholestasis,drug-induced cholestasis, cholestasis of pregnancy, parenteralnutrition-associated cholestasis, primary biliary cirrhosis (PBC),non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis(NASH), liver cirrhosis, alcohol-induced cirrhosis, cystic fibrosis, orliver fibrosis, comprising the step of administering to the patient aneffective amount of the pharmaceutical composition of claim 1.